Enabling Suzuki-Miyaura coupling of Lewis-basic arylboronic esters with a nonprecious metal catalyst

Abstract

The high cost and negative environmental impact of precious metal catalysts has led to increased demand for nonprecious alternatives for widely practiced reactions such as the Suzuki-Miyaura coupling (SMC). Ni-catalyzed versions of this reaction have failed to achieve high reactivity with Lewis-basic arylboron nucleophiles, especially pinacolboron esters. We describe the development of (PPh₂Me)₂NiCl₂ as an inexpensive and air-stable precatalyst that addresses this challenge. Under activation by n-BuMgCl, this complex can catalyze the coupling of synthetically important heteroaryl pinacolborons with heteroaryl halides. Mildly basic conditions (aqueous K₃PO₄) allow the reaction to tolerate sensitive functional groups that were incompatible with other Ni-SMC methods. Experimental and computational studies suggest that catalyst inhibition by substitution of PPh₂Me from Ni(ii) intermediates by Lewis basic reactants and products is disfavored relative to more commonly employed ligands in the Ni-SMC, which allows it to operate efficiently in the presence of Lewis bases such as unhindered pyridines.

Scheme 1. Catalysts for the Ni-SMC and the reaction to prepare Lewis basic heterobiaryls.

Scheme 2. Catalyst discovery by HTE on a bespoke ligand library. See ESI for structures of all ligands.

Scheme 3. Scope of the Suzuki–Miyaura coupling catalyzed by (PPh₂Me)₂NiCl₂ (Ni-1). Reactions were run on 1.0 mmol scale unless noted, isolated yield in parentheses. Equiv. given in scheme refers to the arylboron reagent. The yield in brackets represents assay yield of reaction with 1 mol% Ni on 1 g scale. (a) Reaction run on 1.0 g scale (b) 5 mol% (PPh₂Me)₂NiCl₂/10 mol% PPh₂Me/11 mol% n-BuMgCl (c) 3 mol% (TMEDA)Ni(o-tolyl)Cl/9.9 mol% PPh₂Me as catalyst (d) 90 °C (e) coupling partner was potassium vinyltrifluoroborate (1.5 equiv.).

Scheme 4. Mechanistic experiments on the role of Lewis bases in the Ni-SMC. ^aSee ESI for details.

Scheme 5. Summary of the procedure used to estimate computed Lewis basicities of pyridines 1 and 3. See ESI for computational details, calibration of linear models and thermodynamic data.